Ann Thorac Surg 1995;59:671-675
© 1995 The Society of Thoracic Surgeons
Tranexamic Acid Significantly Reduces Blood Loss Associated With Coronary Revascularization
John A. Rousou, MD,
Richard M. Engelman, MD,
Joseph E. Flack, III, MD,
David W. Deaton, MD,
Susannah G. Owen, AB
Division of Cardiac Surgery, Baystate Medical Center, Springfield, Massachusetts
Accepted for publication November 17, 1994.
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Abstract
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Four hundred fifteen patients undergoing coronary revascularization over a 12-month period were divided into two groups: 209 controls in the first 6 months received no tranexamic acid (TA) before cardiopulmonary bypass and 206 patients in the second 6 months received TA as a hemostatic agent. The demographics and the surgical techniques used were similar in the two groups. With TA there was a significant decrease in blood loss postoperatively, from 1,114.1 mL in the controls to 803.7 mL in those given TA (p < 0.001); in red blood cell use, from 1.7 units/patient in the controls to 0.69 units/patient in those given TA (p < 0.001); in fresh frozen plasma requirements, from 0.23 units/patient in the controls to 0.024 units/patient in those given TA (p < 0.01); and in platelet transfusions, from 1.06 units/patient in the controls to 0.30 units/patients in those given TA (p < 0.01). The percentages of patients not receiving any blood products were 65% in those given TA versus 49% in the controls (p < 0.01). There was no significant difference between the two groups in the incidence of perioperative myocardial infarction, cerebrovascular accidents, pulmonary embolism, or venous thrombosis to clearly suggest hypercoagulability. In this study, TA profoundly affected the coagulopathy associated with bypass in patients undergoing coronary revascularization. It significantly reduced blood loss and blood product transfusions. Any potential increased thrombotic complications could not be clearly demonstrated in this study, but should not be ignored.
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Introduction
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The coagulopathy that develops after cardiopulmonary bypass (CPB) in patients undergoing a variety of cardiac operations remains a potentially serious and costly problem [1, 2]. Numerous attempts have been made to decrease or eliminate specific defects in the coagulation mechanism associated with CPB. Post-CPB platelet dysfunction has been counteracted using desmopressin with beneficial effects [3]. Many investigators, such as Cosgrove and associates [4], Blauhut and colleagues [5], and others [6, 7], have used aprotinin to treat fibrinolysis, with encouraging results.
In this study, we sought to investigate the effects of tranexamic acid (TA), an antifibrinolytic agent given intraoperatively before CPB in patients undergoing coronary revascularization. This agent has been reported previously to be of benefit in patients undergoing cardiac operations [8, 9]. It is readily available in all pharmacies and is relatively inexpensive.
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Pharmacologic Characteristics
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The chemical name for TA is trans-4-(aminomethyl)cyclohexane carboxylic acid [10]. Its empirical formula is C8H15NO2 and its structural formula is:
Tranexamic acid is a competitive inhibitor of plasminogen activation and at higher concentrations a noncompetitive inhibitor of plasmin (Fig 1
). Its actions are similar to those of aminocaproic acid, but is ten times more potent in vitro. Urinary excretion is the main route of elimination by means of glomerular filtration. Only a small fraction of the drug is metabolized and 95% of the dose is excreted in the urine as the unchanged drug.
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Fig 1. . The mechanism of action of tranexamic acid is by competitive inhibition of plasminogen activation, and, at higher concentrations, by noncompetitive inhibition of plasmin, with resulting elimination of fibrinolysis. (TPA = tissue plasminogen activator.)
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Material and Methods
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The patient population consisted of 415 consecutive patients undergoing isolated coronary revascularization over a period of 12 months. In the first 6 months, 209 patients were operated on without the use of TA; in the second 6 months, 206 patients were operated on with the use of TA. For purposes of this study, the first group of 209 patients served as the controls. Excluded from both groups were emergency patients who were taken from the catheterization laboratory straight to the operating room, patients undergoing redo procedures, patients with a known coagulopathy preoperatively, and patients with carotid or peripheral vascular disease, or both, or with renal insufficiency (creatinine level, > 1.5 mg/dL). The surgical techniques used throughout this 12 month period were identical. This included the use of mammary arteries for grafting, the surgical technique, the use of continuous retrograde warm blood cardioplegia for myocardial protection, and the routine use of the Cell Saver (Haemonetics, Braintree, MA) and the autotransfusion system postoperatively. The intraoperative anticoagulation and reversal methods used were standard ones and were identical during both 6-month periods. Heparin was administered at an initial dose of 5 mg/kg, aiming for an activated clotting time of 500 seconds or more, followed by standard maintenance of the time above that level. Reversal of the heparin effects by protamine was governed by the heparin levels in blood (Hepcon; Medtronic HemoTec, Denver, CO). Heparin rebound was monitored by measuring the partial thromboplastin time every 2 hours postoperatively, and was treated with appropriate doses of protamine. The red blood cell transfusion guidelines remained constant throughout the study period, using a hematocrit of 18% intraoperatively and 22% postoperatively as the lowest accepted value before red blood cell transfusion was given. The transfusion of platelets or fresh frozen plasma was restricted to patients with active bleeding postoperatively (> 300 to 400 mL/h x 2 hours or >200 mL/h x 3 hours), and it was not ordered for abnormal values alone.
The TA treatment protocol was similar to that suggested by Karski and associates [9]. Tranexamic acid was given intravenously in a 2-g bolus just before the initiation of CPB, and the rest (8 g) was given by slow infusion during bypass. None was given after CPB was terminated.
All data were collected by retrospective detailed chart reviews. Preoperative and operative characteristics and the demographics for all patients in both groups were recorded, as were the preoperative and postoperative coagulation profiles. Blood loss was recorded as the 24-hour postoperative chest tube drainage. All data on the intraoperative and postoperative red blood cell, fresh frozen plasma, and platelet transfusions were accurately recorded. A number of clinical outcomes were also analyzed, such as mortality, reoperation for bleeding, use of the intraaortic balloon pump, and the discharge hematocrit value. Because of the potential risk of hypercoagulability with the use of antifibrinolytic agents, the highest level of creatine kinase–MB was measured in both groups, and the incidence of perioperative myocardial infarction was also determined, using both electrocardiographic and enzyme criteria. The cause of death in every patient who died was recorded, looking for the percentage of deaths that resulted from myocardial infarction in the immediate postoperative period. Additionally, the incidence of perioperative cerebrovascular accidents, pulmonary embolism, and deep venous thrombosis was recorded and compared between the two groups.
All results are reported as either percentages within each group or as the mean ± the standard error of the mean. Comparisons of results between the two groups were done by the two-sample t test for each variable. A p value of less than 0.05 was considered an indicator of significant difference.
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Results
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The patient demographics for the two groups are shown in Table 1. There were no significant differences in patient age, the sex distribution, or patient weight. There was a slight significant difference in the left ventricular ejection fraction, being lower in the TA group (0.481 ± 0.107) than in the controls (0.52 ± 0.108; p < 0.05). In addition, no major differences between the two groups were noted for a number of preoperative and operative characteristics (Table 2). Preoperative coagulation variables such as the platelet count, prothrombin time, and partial thromboplastin time were similar. The pre-CPB hematocrit, the number of grafts, and the duration of CPB were also not significantly different between the two groups. Only two characteristics showed slight differences that turned out to be significant at p < 0.05. These were the lowest recorded hematocrit during CPB (controls, 18.6% ± 0.20%; TA, 19.5% ± 0.24%) and the percentage use of the internal mammary artery as a coronary graft (controls, 82.3% ± 0.03%; TA, 89.8% ± 0.02%). The data on the postoperative coagulation profile and other variables are shown in Table 3. The platelet count and prothrombin time postoperatively were similar in both groups, but the partial thromboplastin time (controls, 47.4 ± 1.09 seconds; TA 52.6 ± 1.27 seconds) and hematocrit (controls, 27.5% ± 0.23%; TA, 28.4% ± 0.25%) were slightly but significantly higher in the TA group (p < 0.05). The postoperative weight gain was significantly higher in the control group (controls, 3.4 ± 0.21 kg; TA, 2.2 ± 0.20 kg; p < 0.05).
Examination of various clinical outcomes (Table 4) showed no significant differences in mortality (controls, 3.3%; TA, 4.1%), the need for reoperation for bleeding (controls, 4.3%; TA, 4.9%), and use of the intraaortic balloon pump (controls, 6.3%; TA, 9.8%). The discharge hematocrit was similar in both groups (controls, 26.8% ± 0.27%; TA, 27.2% ± 0.31%). There was, however, a significant reduction in postoperative blood loss in the TA group (803.7 ± 44.13 mL) versus that in the controls (1,114.1 ± 44.66 mL; p < 0.001).
Intraoperative and postoperative transfusion data are shown in Figures 2 and 3. Red blood cell transfusions were significantly lower in the TA group (0.69 units/patient) than in the controls (1.27 units/patient; p < 0.001) (Fig 2). Fresh frozen plasma usage (controls, 0.23 units/patient; TA, 0.024 units/patient; p < 0.01) and platelet transfusion (controls, 1.06 units/patient; TA, 0.03 units/patient; p < 0.01) were lower in the TA group (Fig 2). The percentage of patients not receiving any blood products during or after operation was significantly higher in the TA group (65%) than in the controls (49%) (p < 0.01) (see Fig 3).
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Fig 2. . Transfusion of red blood cells (RBC), fresh frozen plasma (FFP), and platelets, in units/patient (intraoperative and postoperative), shown as the mean ± standard error of the mean in each group.
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Fig 3. . Percentage of patients not receiving any blood products during or after operation in both groups.
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Data for evaluation of hypercoagulability are shown in Table 5. The maximal perioperative generation of creatine kinase–MB averaged 39.7 units in the controls versus 44.8 units in the TA group, and the incidence of perioperative myocardial infarction (using both electroencephalographic and enzyme criteria) was 1% in the controls versus 1.5% in the TA group, both of which were not significant differences. Although there was a difference in the incidence of myocardial infarction as a cause of death, being the cause in 25% of the deaths in the control group and in 60% of the deaths in the TA group, this difference did not reach statistical significance either. The incidence of perioperative cerebrovascular accidents, pulmonary embolism, and deep venous thrombosis was quite small in both groups, without significant differences. Long-term myocardial ischemia happened in 3 of the control patients and in 1 patient receiving TA, and the long-term postdischarge mortality was 3.3% in the controls and 2.1% in the TA group, but these differences were not statistically significant.
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Comment
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Cardiopulmonary bypass has been known for a long time to produce a coagulopathy, especially if prolonged. Fibrinolytic activity is an important component of this type of coagulopathy [11]. Increased bleeding as a result of such coagulopathy increases the risk of tamponade, the likelihood of reoperation, the need for transfusion of blood components, costs, and occasionally the risk of death. Recognizing the important effects of fibrinolysis on the coagulation mechanism, various investigators have attempted to supplement existing measures of blood conservation, such as through the use of Cell Savers, membrane oxygenators, and autotransfusion with the use of pharmacologic agents. Vander Salm and associates [12] used 
-aminocaproic acid in a double-blind randomized study in patients undergoing cardiac procedures. They demonstrated beneficial effects from this antifibrinolytic agent, which has an action similar to that of TA. Blauhut and colleagues [5] used aprotinin successfully in patients undergoing CPB. Although Cosgrove and co-workers [4] demonstrated similar benefits in patients undergoing reoperations for coronary revascularization, they raised some concern as to the potential hypercoagulability effects of aprotinin on graft patency.
Tranexamic acid has been studied in Europe since the 1970s [13]. The first publication concerning its use in cardiac surgery patients in the United States was authored by Horrow and associates [8] in 1990. These investigators found clearly beneficial effects of this antifibrinolytic agent in a relatively small number of patients undergoing CPB in terms of decreased bleeding and the need for transfusion. Subsequent to this study, another group of investigators from Toronto [9] reported similar findings in a larger group of patients undergoing cardiac procedures. In our study, we analyzed a uniform population of patients undergoing isolated coronary revascularization procedures. The two groups operated on during two consecutive 6-month periods were similar in terms of the demographics (see Table 1
) and their preoperative and operative characteristics (see Table 2). Excluded from both groups were emergency patients. Any significant differences that existed (ie, higher partial thromboplastin time and higher percentage of patients having mammary artery grafts in the TA group) were found to increase the risk of bleeding and the need for transfusion in that group of patients. With an almost identical discharge hematocrit in both groups, there were significant differences in the postoperative blood loss and the transfusion of blood products such as red blood cells, fresh frozen plasma, and platelets. All of these transfusion requirements plus the blood loss were significantly reduced by TA administration, indicating a beneficial decrease in fibrinolysis during operation. Additionally, the overall percentage of patients not receiving any blood product transfusions was significantly higher in the TA group (65%) than that in the control group (49%). Although dilution (intraoperative hematocrit and postoperative weight gain) was greater in the control group than that in the TA group, we do not believe that that alone totally accounts for the differences seen in the transfusion requirements or bleeding. The implications of these beneficial effects in terms of cost and risk reduction (eg, viral transmission and transfusion reactions) are obvious.
The potential for hypercoagulability to occur with the use of antifibrinolytic agents, as suggested by Cosgrove and associates [4], was taken into account in this study. Except for the higher, but nonsignificant, percentage of the deaths in the TA group due to myocardial infarction, we found no other evidence of hypercoagulability, such as an increased creatine kinase–MB level in the group as a whole, or an increased incidence of cerebrovascular accidents, deep venous thrombosis, or pulmonary emboli. A repeat study with larger numbers of patients in the two groups may be necessary to clarify the issue of hypercoagulability. Mortality and other clinical outcomes were similar for the two groups, except for bleeding and transfusion requirements, as previously noted. In spite of the lack of clear evidence for hypercoagulability, our current approach is the selective use of TA, avoiding its use especially in patients with small coronary vessels or diffuse disease, or both, in patients in whom low graft flows are expected, and in patients with severe peripheral vascular disease, especially when this includes carotid lesions, deep venous thrombosis, or renal insufficiency.
In summary, TA is an antifibrinolytic agent that is inexpensive and readily available. It has been shown to significantly reduce blood loss and blood product transfusion requirements in patients undergoing coronary revascularization. Any potential increased incidence of thrombotic complications as a result of its use with CPB could not be clearly shown.
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Footnotes
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Presented at the Twenty First World Congress of the International Society for Cardiovascular Surgery, Lisbon, Portugal, Sep 12–15, 1993.
Address reprint requests to Dr Rousou, Baystate Medical Center, 759 Chestnut St, Springfield, MA 01107.
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References
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- Cosgrove DM, Heric B, Lytle BW, et al. Aprotinin therapy for reoperative myocardial revascularization: a placebo-controlled study. Ann Thorac Surg 1992;54:1031–8.[Abstract]
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- Alajamo F, Calamai G, Perna AM, et al. High-dose aprotinin: hemostatic effects in open heart operations. Ann Thorac Surg 1989;48:536–9.[Abstract]
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- Cyklokapron®. In: Physicians' Desk Reference. Montvale, NJ: Medical Economics, 1994:1111.
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Abstract
Introduction
